The broad long term goals of this project are: 1.) To develop a detailed understanding of the emergence of S. cerevisiae as an opportunistic pathogen. 2.) To develop S. cerevisiae as a robust model to study the genetically complex phenotypes of pathogenicity and virulence. & 3.) To develop S. cerevisiae as a robust microbial model to study quantitative genetics. The specific aims of this project are: 1.) To determine the genetic basis for the very low in vivo survival-proliferation of the laboratory (S288c) strain and the very high in vivo survival-proliferation of the clinically derived (YJM145) strain S. cerevisiae genetic backgrounds. 2.) To determine the genetic basis for the difference between the non-lethal $288c and lethal YJM145 infection phenotypes. 3.) To examine a large S. cerevisiae population and determine the generality of virulence phenotypes and genotypes. The health relatedness of this project is twofold. First, the identification of the genes that differ between (i) low vs. high in vivo survival-proliferation and (ii) non-lethal vs. lethal strains ofS. cerevisiae is informative with respect to both the emergence of an opportunistic pathogen and what pathogen fungi require to survive-proliferate in and kill the host. Second, examination of the S. cerevisiae population will tell us the generality of virulence and virulence related phenotypes and genotypes. In both cases, we gain insight into the basics of fungal virulence that will aid in the development of antifungal therapies. Unfortunately the underlying basis of fungal pathogenesis is very poorly understood. Using S. cerevisiae, both in vivo survival-proliferation and lethal infections can be examined in ways that are not feasible in more common pathogenic fungi. Understanding the underlying basis of in vivo survival-proliferation and lethal infections aids our understanding of these processes in other pathogenic fungi. We will achieve these goals (i) by mapping the loci/identifying the genes responsible for the in vivo survival-proliferation phenotype and (ii) examining the larger S. cerevisiae population both phenotypically, for virulence and virulence-associated traits, and genotypically, for virulence-related genes.